Prostate cancer specific integrin alphavbeta3 modulates bone metastatic growth and tissue remodeling.

The management of pain and morbidity due to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the alphavbeta3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that alphavbeta3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional alphavbeta3 enabled tumor growth in bone (incidence: 4/4), whereas alphavbeta3 (-), inactive or constitutively active mutants of alphavbeta3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated alphavbeta3 (either inactive of constitutively active), but not those lacking beta3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for beta3 integrin, we next demonstrated that alphavbeta3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated alphavbeta3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development.

Expression of soluble urokinase plasminogen activator receptor may be related to outcome in prostate cancer patients.

The urokinase-type plasminogen activator receptor (uPAR) exists as a GPI anchored glycoprotein (Mr=50-60 kDa) on the surface of various cell types. This receptor can be bound by or cleaved by urokinase. The cleaved receptor, soluble urokinase-type plasminogen activator receptor (suPAR), with an Mr=35 kDa has no known physiological function and can be identified circulating in the blood of normal individuals. Although no function has been characterized, the soluble receptor has been reported to be of clinical significance. The objective of this study is to characterize novel serum markers that can be used for the early detection of prostate cancer and to predict patient prognosis. Thirty-nine patients at the University of Yaounde I, Yaounde, Cameroon, West Africa were examined for prostatic disorders. Of these, 46% were diagnosed with benign prostate hyperplasia (BPH), while 44% of the patients were diagnosed via biopsy with prostate cancer and graded accordingly. Here we show that serum from patients with BPH or prostate cancer contains elevated levels of suPAR. To examine the significance of suPAR as a diagnostic factor, we used a suPAR ELISA kit and compared these results with serum levels of prostate specific antigen (PSA), the current diagnostic marker for prostate cancer. PSA and serum suPAR levels in BPH and cancer patients were greatly elevated in the majority of patients, while others had undetectable levels of either. Serum levels of suPAR were high in cancer patients as well as, although to a lesser degree, in patients with BPH. Cancer patients who died during the follow-up period were found to have consistently higher serum suPAR levels than correlating serum PSA levels. These preliminary findings are the first evaluating serum suPAR levels as a possible diagnostic marker for the early detection of prostate cancer and for the prediction of patient prognosis.

Curcumin inhibits lipoxygenase by binding to its central cavity: theoretical and X-ray evidence.

Many lipoxygenase inhibitors including curcumin are currently being studied for their anti-carcinogenic properties. Curcumin is a naturally occurring polyphenolic phytochemical isolated from the powdered rhizome of the plant Curcuma longa that possesses anti-inflammatory properties and inhibits cancer formation in mice. Recently it was shown that the soybean lipoxygenase L1 catalyzed the oxygenation of curcumin and that curcumin can act as a lipoxygenase substrate. In the current study, we investigated the fate of curcumin when used as a soybean lipoxygenase L3 substrate. By use of X-ray diffraction and mass spectrometry, we found an unoccupied electron mass that appears to be an unusual degradation product of curcumin (4-hydroxyperoxy-2-methoxyphenol) located near the soybean L3 catalytic site. Understanding how curcumin inhibits lipoxygenase may help in the development of novel anti-cancer drugs used for treatment where lipoxygenases are involved.

Platelets govern pre-metastatic tumor communication to bone.

Although the survival rate for early detected cancers is high, once a cancer metastasizes to bone, it is incurable. Interestingly, patients without visible metastases display abnormal bone formation and resorption, suggesting a link between primary cancers and the bone microenvironment prior to metastasis, and this link likely facilitates preparation of the pre-metastatic niche. We hypothesized that communication with the primary tumor would result in bone remodeling alterations, and that platelets could facilitate this communication. By using three tumor models, we demonstrate that primary tumor growth stimulates bone formation measured by microcomputed tomography. Further, platelet depletion prevented tumor-induced bone formation, highlighting the importance of platelets in the communication between tumors and the bone microenvironment. Finally, we determine that platelets sequester a variety of tumor-derived proteins, TGF-ß1 and MMP-1 in particular, which regulate bone formation. Thus, our data reveal that platelets function as mediators of tumor-bone communication prior to metastasis.